SWOG-9321 Melphalan, TBI, and Transplant vs Combo Chemo in Untreated Myeloma

Multiple Myeloma Clinical Trial

Official title:

Standard Dose Versus Myeloablative Therapy for Previously Untreated Symptomatic Multiple Myeloma, A Phase III Intergroup Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00002548
• Other study ID #: SWOG-9321
• Secondary ID: SWOG-9321CLB-931
• Status: Completed
• Phase: Phase 3
• First received: November 1, 1999
• Last updated: March 5, 2015
• Start date: January 1994
• Est. completion date: November 2006

Study information

• Verified date: March 2015
• Source: Southwest Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Combining chemotherapy and radiation therapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy and radiation therapy and kill more cancer cells. It is not yet known which treatment regimen is more effective for multiple myeloma.

PURPOSE: Randomized phase III trial to compare the effectiveness of melphalan, total-body irradiation, and peripheral stem cell transplantation with that of combination chemotherapy in treating patients who have previously untreated multiple myeloma.

Description:

OBJECTIVES:

• Compare tumor cytoreduction achieved with VBMCP (vincristine/carmustine/melphalan/cyclophosphamide/prednisone) vs myeloablative melphalan (L-PAM) and total-body irradiation (TBI) with peripheral blood stem cell (PBSC) rescue in symptomatic myeloma patients with stable or responding disease after induction therapy with VAD (vincristine/doxorubicin/dexamethasone) followed by high dose cyclophosphamide plus filgrastim (G-CSF).

• Compare the efficacy of interferon alfa vs no maintenance therapy in those patients achieving at least 75% cytoreduction to either VBMCP or myeloablative therapy with PBSC rescue.

• Assess allogeneic bone marrow transplantation following the same myeloablative regimen of L-PAM/TBI in patients up to age 55 with an HLA-compatible, MLC-nonreactive donor. (As of 8/1/97, permanent partial closure)

• Determine whether myeloablative therapy with PBSC rescue can extend the duration of survival by 33% compared to results from standard dose VBMCP.

• Evaluate the toxic effects and possible long term side effects, including development of myelodysplastic disease and/or acute myeloblastic leukemia, associated with these treatments.

OUTLINE: This is a randomized study. Patients are registered at 5 different points, with stratification occurring at some of these registrations.

• Registration I: Induction I

• Registration II: Induction II. Patients are stratified according to stage of disease (I/II vs IIIA vs IIIB), beta-2 microglobulin at diagnosis (less than 6 micrograms/mL vs at least 6 micrograms/mL), and response to Induction I (75-100% regression vs 50-74% regression vs less than 50% regression vs not applicable).

• Registration III: Patients are randomized to allogeneic bone marrow transplant (BMT) (this arm closed as of 8/1/97) or autologous BMT. Patients are stratified according to treatment received (high dose cyclophosphamide (CTX) and peripheral blood stem cells (PBSC) prior to autologous BMT vs prior to chemotherapy) and beta-2 microglobulin at this registration (less than 2 micrograms/mL vs no greater than 3 micrograms/mL vs unknown).

• Registration IV: Patients are randomized to maintenance therapy or no further therapy. Those patients who are randomized to maintenance therapy are stratified according to treatment (autologous BMT vs chemotherapy vs chemotherapy followed by autologous BMT) and response to treatment (75-99% regression vs complete response).

• Registration V: Patients receive autologous BMT as in registration III. Patients are stratified according to prior best response (50% or better vs less than 50% vs not applicable), duration of chemotherapy (at least 6 months vs less than 6 months), and progression after therapy (chemotherapy vs interferon alfa vs observation).

• Induction I: Patients receive vincristine IV and doxorubicin IV by continuous infusion on days 1-4 and dexamethasone IV or orally on days 1-4, 9-12, and 17-20. Treatment repeats every 5 weeks for up to 4 courses. Patients with progressive disease after 2 courses proceed to PBSC stimulation/harvest.

Allogeneic BMT arm is permanently closed as of 8/1/97.

• Autologous BMT: Therapy begins 4-8 weeks following high dose cyclophosphamide. Patients receive melphalan IV over 1 hour on day -5 and total body irradiation twice a day on days -4 to -1. PBSC are reinfused on day 0. G-CSF SQ is administered beginning on day 1 until blood counts recover.

• Chemotherapy: Patients receive vincristine IV, carmustine IV, and cyclophosphamide IV on day 1, oral melphalan on days 1-4, and oral prednisone on days 1-7. Treatment repeats every 5 weeks for at least 12 months.

Patients who have at least a 75% response to autologous BMT or chemotherapy are randomized to maintenance vs no further therapy. Patients who progress on chemotherapy proceed to autologous BMT (registration V).

• Maintenance therapy: Therapy begins between 5 and 12 weeks after PBSC rescue. Patients receive interferon alfa SQ three times a week. Treatment continues for 4 years in the absence of disease progression or unacceptable toxicity.

Patients who progress on chemotherapy undergo an autologous BMT within 8 weeks after the last course of chemotherapy.

Patients who are randomized to receive no further therapy are observed for 1 year.

PROJECTED ACCRUAL: A total of 500 patients will be randomized over about 4 years to autologous transplantation vs chemotherapy as follows: about 250 patients/year will be accrued for induction of whom 200 will achieve at least stable disease, 125 will be randomized, and 15 will have a suitable donor for allogeneic transplant (as of 8/1/97, allogeneic arm of study is closed). Approximately 300 patients are expected to be randomized to maintenance vs no further therapy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 899
• Est. completion date: November 2006
• Est. primary completion date: October 2003
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

DISEASE CHARACTERISTICS:

• Newly diagnosed, active multiple myeloma of any stage requiring treatment

• Smoldering myeloma (Durie-Salmon stage I) must have a 25% or greater increase in M component levels and/or Bence-Jones protein excretion or development of symptoms

• Quantifiable M component of IgG, IgA, IgD, IgE, and/or urinary kappa or lambda light chain (Bence-Jones protein) excretion required

• Plasmacytosis of at least 30% allowed for non-secretory disease or secretory disease without quantifiable protein

• IgM peaks excluded

• Evaluation of siblings as potential allogeneic bone marrow transplant donors required for patients 55 years of age and younger (As of 8/1/97, permanently closed)

• HLA followed by DR and MLC testing required

• Renal failure, even on dialysis, eligible provided:

• Cause is attributed to myeloma (Bence-Jones protein or hypercalcemia)

• Duration does not exceed 2 months

• If medically appropriate, the following conditions should be treated prior to registration:

• Pathologic fractures

• Pneumonia at diagnosis

• Hyperviscosity with shortness of breath

PATIENT CHARACTERISTICS:

Age:

• 70 and under

Performance status:

• SWOG 0-2 (SWOG 3 or 4 based solely on bone pain allowed)

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• See Disease Characteristics

Cardiovascular:

• Normal ejection fraction by ECHO or MUGA

• No myocardial infarction within 6 months

• No unstable angina

• No difficult to control congestive heart failure

• No uncontrolled hypertension

• No difficult to control arrhythmias

• No history of chronic cerebral vascular accident

Pulmonary:

• No history of chronic obstructive or restrictive pulmonary disease

• Pulmonary function studies and DLCO at least 50% of predicted except for demonstrated myeloma involvement on bronchoscopy and/or open lung biopsy

Other:

• No uncontrolled diabetes

• No significant comorbid medical condition

• No uncontrolled, life-threatening infection

• No prior malignancy within 5 years except adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix

• No prior malignancy treated with cytotoxic drugs used on this protocol

• Not pregnant or nursing

• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy except local radiotherapy provided the following cumulative dose limits for prior dose plus potential TBI dose on protocol are not exceeded:

• Less than 5,000 cGy to bone

• Less than 4,000 cGy to mediastinum, heart, small bowel, brain, and spinal cord

• Less than 2,000 cGy to the liver

• Less than 1,500 cGy to the kidney and lungs

Surgery:

• Not specified

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Biological:
• recombinant interferon alfa
3 million units/m2 SQ Monday-Wednesday -Friday (3 times a week)

Drug:
• carmustine
20 mg/m2 I.V. day 1 q 35 days
• cyclophosphamide
1.5 g/m2 in 100 ml of D5W, IV intravenously over 1 hour every 3 hour x 3 (total dose 4.5 g/m2)
• dexamethasone
40 mg/day PO or IVPB days 1-4, 9-12, 17-20 q 5 weeks
• doxorubicin hydrochloride
10 mg/m2/day continuous 1 - 4 q 5 weeks
• melphalan
140 mg/m2 is given IV within 30 minutes of constitution on Day -5
• prednisone
40 mg/m2 PO days 1-7 q 35 days
• vincristine sulfate
0.5 mg/day continuous 1 - 4 q 5 weeks

Procedure:
• allogeneic bone marrow transplantation
day 0
• autologous bone marrow transplantation
day 0
• peripheral blood stem cell transplantation
day 0

Radiation:
• radiation therapy
administered in fractionated doses of 150 cGy, 6 - 10 hours apart bid, on Days -4, -3, -2, and -1 (Total 1,200 cGy)

Locations

Country	Name	City	State
United States	CCOP - Ann Arbor Regional	Ann Arbor	Michigan
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	New England Medical Center Hospital	Boston	Massachusetts
United States	Albert Einstein Comprehensive Cancer Center	Bronx	New York
United States	Robert H. Lurie Comprehensive Cancer Center, Northwestern University	Chicago	Illinois
United States	Veterans Affairs Medical Center - Lakeside Chicago	Chicago	Illinois
United States	Ireland Cancer Center	Cleveland	Ohio
United States	CCOP - Geisinger Clinic and Medical Center	Danville	Pennsylvania
United States	CCOP - Colorado Cancer Research Program, Inc.	Denver	Colorado
United States	CCOP - Iowa Oncology Research Association	Des Moines	Iowa
United States	CCOP - Duluth	Duluth	Minnesota
United States	CCOP - Evanston	Evanston	Illinois
United States	Indiana University Cancer Center	Indianapolis	Indiana
United States	Veterans Affairs Medical Center - Indianapolis (Roudebush)	Indianapolis	Indiana
United States	CCOP - Kalamazoo	Kalamazoo	Michigan
United States	CCOP - Marshfield Medical Research and Education Foundation	Marshfield	Wisconsin
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Veterans Affairs Medical Center - Milwaukee (Zablocki)	Milwaukee	Wisconsin
United States	University of Minnesota Cancer Center	Minneapolis	Minnesota
United States	CCOP - Ochsner	New Orleans	Louisiana
United States	NYU School of Medicine's Kaplan Comprehensive Cancer Center	New York	New York
United States	Veterans Affairs Medical Center - New York	New York	New York
United States	CCOP - Illinois Oncology Research Association	Peoria	Illinois
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Hahnemann University Hospital	Philadelphia	Pennsylvania
United States	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	University of Rochester Cancer Center	Rochester	New York
United States	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota
United States	CCOP - Scottsdale Oncology Program	Scottsdale	Arizona
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida
United States	CCOP - Toledo Community Hospital Oncology Program	Toledo	Ohio
United States	CCOP - Carle Cancer Center	Urbana	Illinois

Sponsors (4)

Lead Sponsor	Collaborator
Southwest Oncology Group	Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (13)

Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD, McCoy J, Moore DF Jr, Dakhil SR, Lanier KS, Chapman RA, Cromer JN, Salmon SE, Durie B, Crowley JC. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: fina — View Citation

Crowley J, Fonseca R, Greipp P, et al.: Comparable survival in newly diagnosed multiple myeloma (MM) after VAD induction with high dose therapy using melphalan 140mg/m2 + TBI 12 Gy (MEL+TBI) versus standard therapy with VBMCP and no benefit from interfero

Crowley JJ, McCoy J, LeBlanc M, et al.: Extreme regression: a statistical technique for finding good or poor prognostic groups, illustrated using myeloma patient data from Intergroup trial S9321. [Abstract] Blood 104 (11): A-5202, 2004.

Desika R, Salmon S, Anderson K, et al.: Planned melphalan-total body irradiation (MEL-TBI) - based allogeneic transplantation for multiple myeloma (MM) up to age 55: an intergroup experience (CALGB, ECOG and SWOG) under the auspices of the Southwest Oncol

Greipp PR, Jacobson JL, Crowley JJ, et al.: BETA 2 microglobulin (beta 2M) and plasma cell labeling index (PCLI) constitute a strong prognostic index in the SWOG intergroup transplant trial S9321: observations on gender and age. [Abstract] Blood 96 (11 pt

Greipp PR, Kumar S, Blood EA, et al.: A simple classification to identify poor-risk untreated myeloma. [Abstract] Blood 100 (11 Pt 1): A-2351, 598a, 2002.

Lee CK, McCoy J, Anderson KC, et al.: Long-term follow-up of previously untreated symptomatic myeloma patients treated with myeloablative therapy and sibling-matched allogeneic transplantation of the SWOG study 9321. [Abstract] Blood 100 (11 pt 1): A-1644

Rajkumar V, Leong T, Fonseca R, et al.: Bone marrow angiogenesis has prognostic value in multiple myeloma: an Eastern Cooperative Oncology Group study. [Abstract] Proceedings of the American Society of Clinical Oncology 18: A68, 19a, 1999.

Rimsza LM, Campbell K, Dalton WS, Salmon S, Willcox G, Grogan TM. The major vault protein (MVP), a new multidrug resistance associated protein, is frequently expressed in multiple myeloma. Leuk Lymphoma. 1999 Jul;34(3-4):315-24. — View Citation

Santana-Davila R, Crowley J, Durie B, et al.: Genetic polymorphisms associated with clinical outcome in the intergroup trial S9321, comparing high dose therapy with standard dose therapy for myelomaon, on behalf of ECOG, SWOG, CALGB, and the Bank on a Cur

Tian E, Bumm K, Xiao Y, et al.: A protocol for triple color interphase FISH on archived bone marrow biopsies from myeloma prepared with precipitating fixatives. [Abstract] Blood 96 (11 pt 1): A-665, 155a, 2000.

Van Ness BG, Crowley JC, Ramos C, et al.: SNP genotypes show association with common toxicities during both VAD induction and high dose melphalan with autologous transplant support in intergroup trial S9321 for myeloma: from the Bank on a Cure. [Abstract]

van Ness BG, Ramos C, Kumar V, et al.: Analytical approaches for the BOAC SNP panel association with progression free survival in myeloma. [Abstract] Blood 112 (11): A-2715, 2008.

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	survival		3 years from randomization	No